Nicole: Good evening and welcome to tonight's webinar, integrating non-invasive prenatal testing or NIPT into general practice, value to the patient, limitations and counselling considerations. This is the final webinar of this series. My name is Dr Nicole Hall. I am a GP at Holsworthy in New South Wales and a GP VMO in high-risk antenatal care at Liverpool Hospital. Thanks again to Alumina for bringing us this series.
Nicole: To start tonight's webinar, I would like to make an acknowledgement of country. We recognise and acknowledge the traditional custodians of the land and sea on which we live and work. We pay our respects to Elders; past, present and emerging. I will now run through a few housekeeping notes. This webinar is being recorded and will be made available for you later in the week. To interact with us today, you will need to use the Zoom control panel. If you cannot see a panel like this on the slide, hover your cursor over the bottom section of the shared presentation screen and the panel should appear. The control panel allows you to select your preferred audio settings like which speaker you are using and also to interact with the presenters. We have put all attendees on mute tonight to ensure that learning will not be disrupted by any background noise. As this is a webinar, we are unable to see you as participants, so please interact with us using the Q&A box at the bottom of your screen.
Nicole: Please do not enter any personal information aside from your name and question as all attendees will be able to see this. If someone else has asked a question that you would like answered, please give it a thumbs up. Questions that have more likes will move to the top of the list to be asked. We will have a dedicated Q&A session at the end of the webinar, but please ask questions throughout and we will try to answer them as we go along.
Nicole: I would like to introduce this evening's presenter, Belinda Dopita. Belinda is a HGSA certified genetic counsellor with over 19 years of clinical experience. She completed her undergraduate degree at ANU and her Postgraduate Diploma in Genetic Counselling in Melbourne. She worked at the Center for Human Genetics in Boston, USA. After returning to Australia, she completed her master's degree in genetic counselling, studying position knowledge of genetics whilst working at the Children's Hospital of Westmead. She currently works at the ACT Genetics Service in both general and cancer genetics, and she also habits a private practice, Comprehensive Genetic Counselling, which she founded in 2014. Her private practice has grown, and she offers a combination of face-to-face, Skype and phone consultations nationally. She has a particular interest in pre-pregnancy and pre-genetic counselling and is responsible for discussing NIPT results that come back abnormal and also reproductive carrier genetic screening Australia wide. She is currently the ACT state representative for the Human Genetics of Australasia and has a long history of service with the HGSA. She also has a background in psychology and has previously worked with children in a number of areas. And, she is also interested in genetic counselling of children and young adults. She has three children which keep her busy, enjoys horse riding, dining out at any free time she can get to herself. Welcome.
Belinda: Hi there and thank you so much for that lovely introduction Nicole. I will just get my slideshow started. I guess, I wanted to start by talking a little bit about pre- and post-test genetic counselling for NIPT and I have arranged a few vignettes that we can look at and scenarios that may come across your practice. We will have questions that you can interrupt me as we go, and we will also have some question time at the end.
Belinda: I hope, by the end of this session that we will have had a chance to talk about considerations, genetic counselling considerations prior to offering NIPT as well as the considerations once the results are back. I have also collated a number of resources that may be of help to you as well.
Belinda: So, when we talk about what is genetic counselling, it is a process, a process by which we help people to understand and adjust to the medical, psychological and familial implications of genetic disease and help them make decisions in accordance with their own values. So, really it is an exercise in risk calculation, psychosocial assessment, education about medical and genetic information and really a communication process.
Belinda: This is not unique to genetic counsellors and it is something you are probably doing on a regular basis. We explain screening and testing options, we talk about risk and discuss risk, we confirm and explain diagnoses. We talk about options available to people given results of certain tests and identify community resources that might be helpful. We provide individualized counselling and support. Unlike traditional areas of medicine, genetic counselling often involves a couple or a family and so, sometimes it becomes a little bit more complex.
Belinda: I have put together a couple of cases that you might have come across as we go. So, here is Megan. She is a 30-year-old woman in her first pregnancy, and she has come along to talk to you because she just wants that test, the test for everything and actually, this is not an uncommon request.
Belinda: I think the media further propagates this idea that there is genetic testing that can give you all the answers. Although technology is improving dramatically, 2% to 3% of all babies are born with a congenital problem, and many of these would not be detectable by genetic testing. I think the best place we can start is to further understand Megan's question and by looking at maybe where her anxiety is coming from, and an opportunity to put her risk in context.
Belinda: So, I would first talk to Megan about her family history. Is there anything about her or her family history that is making her particularly concerned.
Belinda: I would also want to know about her ethnic background because we are still considering genetic testing for people from certain ethnic backgrounds. For example, people who have a Mediterranean or Asian background would consider screening for thalassaemia, people with Caucasian background we think about cystic fibrosis.
Belinda: But most of all, I would also like to know the basis of her concern, why is she worried or anxious? Pregnant women talk and often they are getting their first information about prenatal screening from their peers. It may just be that her neighbour had some sort of testing and that is what she wants as well.
Belinda: At 30 years of age, Megan's risk of having a child with a chromosome abnormality is 1 in 385. So, I try and reflect the information that I am giving in terms of fractions as well as percentages, that is a 0.3% chance of having a baby with a chromosome problem. And, then I try and reversed that statistic as well, by saying that there is a 99.7% chance she would not have a baby with a chromosome problem. There are options available to her for screening for conditions like down syndrome, including non-invasive prenatal testing, NIPT and I guess throughout this talk, I kind of use that interchangeably with cell-free fetal DNA testing.
Belinda: The basic principle of prenatal screening is to offer safe and accessible testing for pregnant women in order to identify those women who are at increased risk of having a baby affected by chromosomal or genetic conditions.
Belinda: The basic premise for NIPT is to reduce the number of invasive tests being performed which incur a risk of miscarriage while still capturing as many women that are in that high-risk category to give them information.
Belinda: Royal Australian and New Zealand College of Obstetricians and Gynaecologists have recommended that all pregnant women be informed about available options for screening for chromosome abnormalities.
Belinda: But they also note that this testing is not considered diagnostic, so confirmatory testing is required for any abnormal results.
Belinda: They also note in these guidelines from 2018 that the presence of any fetal structural anomaly remains an important indication for invasive prenatal testing, even in the presence of a low-risk cell-free fetal DNA result.
Belinda: One of the challenges I have come across in more recent times is the issue of gender.
Belinda: And pre-test counselling for NIPT needs to include informed decision making regarding fetal sex.
Belinda: Women need to be given the choice to either opt in or out of receiving information about gender and I feel at the moment, culturally there is a big push for people to find out the agenda, so they can have these gender reveal parties.
Belinda: But there are alternative ways to determine gender for that purpose. Couples need to understand that, by choosing to reveal the gender they could also find out about sex chromosome aneuploidies, which are much milder conditions than some of the other trisomy’s screened.
Belinda: When I am giving results following high-risk NIPT results for sex chromosome aneuploidies, it is not uncommon for people to say to me that if they had known the condition would be so mild or if they had known this was a potential result, they would have chosen not to find out the gender through NIPT, so it is an important consideration and an important factor to discuss in that pre-testing process.
Belinda: Another factor is that not all companies that are offering NIPT offer the same test.
Belinda: As we have heard some of the companies offer just the five standard chromosome conditions, involving chromosomes 13, 18, 21 and the sex chromosomes while others are offering an inclusion of chromosome microdeletion as well, and some companies are offering all 23 chromosomes. So rare autosomal trisomies are also known as RATs and these are chromosome aneuploidies other than the standard 13, 18, 21 and the sex chromosomes.
Belinda: Most RATs are a result of confined placental mosaicism, so that is only seen in the placenta, and not actually in the cells of the baby.
Belinda: Of those that are real, most resulting miscarriage before 10 to 12 weeks gestation, pregnancy that progresses beyond this period may have mosaicism.
Belinda: And if this occurs, there is an increased chance that a baby may have physical and intellectual problems, so there is certainly a role and a place for testing for RATs.
Belinda: Whether it is offered to the general population or whether it is something that is used when maybe a structural foetal abnormality is identified on ultrasound.
Belinda: First, it is part of that decision making process and a part of discussing the tests that are available to couples.
Belinda: So, in that pre-test screening, the pre-test counselling, we really need to talk a little bit about what the test is that we are discussing, what is NIPT, and what are the alternative options available.
Belinda: The possibility of test failure and maybe a re-sample might be required. We need to talk about the limitations and implications of the testing and a discussion about testing for fetal sex and sex chromosome aneuploidies.
Ideally it would be helpful to have a brief exploration about a person's views of having a baby with a chromosome problem and potentially even their views regarding termination of pregnancy. It is probably important to note too that NIPT can sometimes be a particularly attractive test to people who live remotely and maybe cannot access as many health services and want extra information about their pregnancy.
Belinda: It is also really good for people who may not be considering termination of pregnancy.
Belinda: And since the NIPT gives a broadly accurate result, without any increased risk of miscarriage that you may have by performing a diagnostic test like a CVS or an amniocentesis. It may provide helpful information for individuals.
Belinda: When we talk about post-test counselling, I guess some of the important things to consider are the interpretation of the results in the first place. Positive test results are usually reported in either terms of saying a positive result or aneuploidy is detected, or they might give a probability. Following a positive test, patients should be referred for post-test counselling which should include a discussion about the positive predictive value of the cell-free fetal DNA test as a screening test, including a discussion about the possibility of a false positive result. They should be offered diagnostic testing to verify the result, especially for women who are considering stopping the pregnancy.
Belinda: It is important to remember that women who do not want to stop the pregnancy could choose to test a baby after birth for diagnostic purposes if they wish, and that is completely reasonable and very easy to organize as well.
Belinda: So, when we are looking at sensitivity and specificity of tests, I have just given a few numbers that broadly sort of represent the sensitivity and specificity of NIPT for these conditions.
Belinda: And these numbers look really good, and they are, but when a screen is marketed with a 99% detection rate for down syndrome, even providers can make the mistake of thinking that that's close enough to 100% that it might as well be considered diagnostic.
Belinda: It is important to consider that 99% detection rate does not apply to an individual's result, but rather to the entire screened population.
Belinda: And so, a high-risk result for women, maybe over the age of 35 or have had a prior chromosome abnormality, might have a higher prior risk and therefore, the positive predictive value, so the chance that the test results as true positive would be higher than those for women at a lower prior risk.
Belinda: Individuals need to understand prior to having NIPT that a result can come back normal and there is still a small chance a baby might have a chromosome abnormality. If the patient cannot accept this degree of uncertainty, then diagnostic testing would need to be discussed.
Belinda: The positive predictive value of test is dependent not only on the sensitivity and specificity of a test, but it is also dependent on the prevalence of the condition in the population.
Belinda: This is a really fabulous website. It provides a calculator where you can enter the details of your patient meaning their patient's age and which aneuploidy has resulted in a higher risk for that particular patient, and it will calculate the positive predictive value for you, so the chance that that result represents a true positive result for the fetus.
Belinda: And if it is not provided on the report already, this gives you a good insight into, I think a valuable statistic that can really help people interpret their results.
Belinda: The positive predictive value for a woman who is 25 who has had a high-risk result for down syndrome is approximately 51%, so that is a 49% chance that the fetus is not affected.
Belinda: However, if that was a 35-year-old woman, the positive predictive value would be 79% and for a 45-year-old woman, the positive predictive value is 98%.
Belinda: The positive predictive values change for different chromosome aneuploidies as well and as you can see, NIPT performs very well for down syndrome or trisomy 21.
Belinda: Positive predictive value for trisomy 18 is 69% compared to that for trisomy 13 which might be 51%. Positive predictive value for a 40-year-old, who may have a high risk for Turner syndrome, so that is one X chromosome instead of standard two, is 41% which means you still may have a higher chance that the baby is unaffected.
Belinda: And then the positive predictive value for a 40-year-old with a high risk of Klinefelter syndrome, so XXY is 52% given this calculator.
Belinda: So you can see that, despite looking at great sensitivity and specificities, we need to also consider what was our patients priorities, how old are they and what condition are we getting an increased risk for because no conditions are equal here.
Belinda: So non-invasive tests typically measure things like maternal serum markers that are interpreted in the context of maternal age and nuchal translucency.
Belinda: CVS and amniocentesis on the other hand are providing actual chromosome analysis which can either confirm or disprove an abnormal screening test, but they are associated with a small risk of pregnancy loss in the range of about 0.5% to 1%. So, NIPT shares features of both screening and diagnostic tests.
Belinda: In my experience though, when we were just offering maternal serum screening, the population never confused the fact that that was a diagnostic test. They were very clear and understood that this was a screening test that was being offered, but now that NIPT has so much better sensitivity and specificity, I think patients feel that it is more likely to be diagnostic and this is just not the case.
Belinda: Many people believe that it could replace the CVS or an amniocentesis and that is not the case either, because a CVS or an amniocentesis will provide information about other conditions other than fetal aneuploidy as well.
Belinda: I guess, this is also a really important time to mention the valuable nature of ultrasonography as well and NIPT test should not replace any ultrasonography people should still be referred for their 12-week morphology scans and the 20-week morphology scans because they are providing a lot of additional information that an NIPT result would not give you and information about other conditions and placental health as well.
Belinda: So, going back to our friend Megan who originally saw you in the first place, she has had NIPT and her result has come back normal.
Belinda: How do we disclose this result? I think that it is important to remember that using the term positive and negative in some circumstances, people get confused. In some circumstances, a positive result means good news.
Belinda: So, in this circumstance, I would phrase the information in terms of, this is a really reassuring result and no abnormalities were detected in chromosomes 13, 18, 21 or the X or Y chromosomes. It is a standard male chromosome pattern, but we must remember that this is a screening test, and so a chromosome abnormality cannot be completely excluded.
Belinda: And I would remind her that it is still important to attend her 12-week and 20-week ultrasound and that these ultrasounds can give additional information about her baby and her pregnancy.
Belinda: So, this is Debbie. Debbie's result has been reported as a failed test and the laboratory have requested a repeat sample.
Belinda: Now a proportion of NIPT samples fail to produce an interpretable result, and that can be for a variety of reasons including low fetal fraction.
Belinda: Now, fetal fraction increases with gestational age and correlates inversely with maternal weight, so it could be a problem related to the recorded gestation and the timing of her test. It could be related to Debbie's BMI.
Belinda: Sometimes, however, this can be because of specimen-related issues or suboptimal data quality.
Belinda: Reported failure rate varies amongst NIPT _____, but it seems to vary between about 1.6% and 6.4%.
Belinda: Now, we can organise to perform a redraw for Debbie.
Belinda: And in approximately 50% of cases, however, the recollected sample will give you a result.
Belinda: If the recollection analysis does not yield a result, there is emerging evidence to suggest that it may be associated with a fetal aneuploidy.
Belinda: In fact, one study showed that about 8% of patients overall had a failed testing and this increased to 16% when there was a known fetal aneuploidy there. Now, that is especially cases of trisomy 13, trisomy 18, and triploidies.
Belinda: Although the degree of this risk has not been fully established. A repeat NIPT result as I said, is successful approximately somewhere between 50% and 80% of the time. It depends on the company, it depends on the underlying reasons for the failure in first place. The American College of Medical Genetics and Genomics has recommended that invasive testing could be offered following a failed NIPT result.
Belinda: So, this is Sarah. Sarah is a 44-year-old woman who has had an abnormal NIPT result, showing an increased risk for trisomy 21 or Down syndrome. The positive predictive value in this case is 98%.
Belinda: Now, this consultation with Sarah is likely to be an emotionally charged situation and the words that you choose to use here are going to be important, because they will set the scene for the future and the ongoing relationship with Sarah.
Belinda: Ideally, we would like to see Sarah in person to discuss these results. That is not always possible.
Belinda: But, if it is, then she is going to be attending with heightened anxiety, knowing that something is not right.
Belinda: I would talk to her and say that the result is back and unfortunately, it is not reassuring.
Belinda: The result indicates an increased chance that the baby has Down syndrome and as she will remember the NIPT was a screening test, and it was not diagnostic. It was designed to identify people who are at an increased chance of having a baby with trisomy and may benefit from additional testing.
Belinda: There is a chance that this could be a false positive result.
Belinda: And what we have learned about giving bad news is that from the time the news is delivered, very little information is heard after that.
Belinda: So, slowing down what we are saying and spending some time sitting in silence with Sarah is going to be really helpful for her as she absorbs the information and has an opportunity to respond to that emotional impact of the news that she has just heard.
Belinda: And I would even spend a little bit of time saying I know I have given you a lot of information, right now, but how are you coping with this information.
Belinda: I would discuss Down syndrome. I had asked her if she has come across people with Down syndrome before, or as she heard of Down syndrome or seen people with Down syndrome before.
Belinda: I would explain that, to verify this result, we would need to perform a diagnostic test, either in a pregnancy or once the baby is born.
Belinda: Diagnostic testing in a pregnancy would mean either an amniocentesis or a CVS to look at the baby's chromosomes to confirm whether the baby has two copies of chromosome 21 or three. It can also look at the other 22 pairs of chromosomes to see if there is any other extra information or missing information across those chromosomes.
Belinda: I would say to her that some people may choose to verify this result because they might be considering stopping or terminating a pregnancy based on this result, while others might choose to have testing just to inform themselves about the future.
Belinda: And help prepare for the arrival of the baby.
Belinda: With an amniocentesis or CVS, there is a small risk of miscarriage, I would usually quote a 0.5% to 1% risk of miscarriage, so for women who are sure that they would not alter the outcome of their pregnancy, they may choose not to pursue any diagnostic testing at the time, and they can test the child when it is born.
Belinda: And I would let her know that this choice is hers and her partners and that I support them with whichever decision that they might choose.
Belinda: I would ask her if prior to having screening, she had considered what she might do if she were to get an abnormal result.
Belinda: I would want to support her with giving her some additional written material because again people cannot absorb an awful lot of material at the time when they are in shock and it is a lot of pressure to feel that they have to remember all the information to share with the other people in their lives.
Belinda: Whether it is their partner or whether it is somebody that is going to be a support with them through this next period of decision making.
Belinda: When we look at the discordance between an NIPT result and a karyotype, there is a number of possible causes and so verifying the diagnosis is essential if parents are considering termination of pregnancy.
Belinda: Because in the general population, as many as 20% of positive NIPT results may be false positives, so the proportion will be higher for trisomies 18 and 13 and the sex chromosome abnormal aneuploidies.
Belinda: Remember that cell-free fetal DNA is mainly placental in origin, and so, therefore, the discrepancy could be due to confined placental mosaicism, and that may be a factor in deciding between CVS and amniocentesis.
Belinda: Keeping in mind as well though, a CVS is done earlier, which means the difference between CVS and amniocentesis may also be a difference in decision making between the method of termination of pregnancy. It could mean the difference between performing a D&C (dilatation and curettage) as opposed to an induction of labour and delivery of the baby.
Belinda: And so, these are all factors that come together in part of this sort of decision-making process, and I think information that is key to these women making decisions like this.
Belinda: Also because of the circulating cell-free DNA as a combination of maternal and placental and abnormal maternal chromosome makeup could lead to discordant results.
Belinda: As could maybe fetal demise of an unaffected fetus, so if there had been a twin pregnancy and one of them had demised or fetal mosaicism. So, these cases are not really false positives. They are detecting an abnormality that is truly present. It just is not necessarily present in the fetus.
Belinda: So, this is actually a case that happened reasonably recently for me. Maya received a result indicating a high-risk NIPT result for Turner syndrome, the positive predictive value was about 25%.
Belinda: Whenever I see a high risk for Turner syndrome, when I am talking through the result, I also like to include information like that Turner syndrome comes with a high risk of miscarriage, because it is not uncommon that a woman who presents for her CVS or her amniocentesis attends an ultrasound they may see that she has miscarried already and so it is valuable information to help prepare people for that possibility, but in this case, she had had an ultrasound which had confirmed a viable pregnancy.
Belinda: In addition, the ultrasound was suggestive of a male fetus and prenatal diagnoses had been organised in terms of CVS before I had a chance to talk with her.
Belinda: So, what could be going on?
Belinda: I guess, this is a really lovely example I think about communicating with other people involved in Maya's care. I had contacted the laboratory because there was discordance with her gestational dates.
Belinda: So, I contacted the laboratory and actually recalculated the algorithm based on the correct date, to see if that had factored into the high-risk result. It hadn't.
Belinda: I guess, we could also have communication with the person performing the ultrasound to get a bit of a feeling of how clear was the ultrasound? Was it under good circumstances? How likely do they think that the ultrasound was correct? We know that up to 1:500 NIPT fetal sex results are expected to be discordant as that Y chromosome is really small and repetitive.
Belinda: It could be that there is a change or copy number variant on that Y chromosome or some sort of structural variant that is undetectable.
Belinda: It could be that there may be a Turner syndrome, so just one X placental Turner syndrome cell lines, so that could have been a demise co-twin or alternatively, there could be placental mosaicism that could be present in terms of confined placental mosaicism or true fetal mosaicism.
Belinda: But the only way we will get to the bottom of this is through diagnostic testing, whether that be either in the form of prenatal testing or testing the child at birth.
Belinda: I would also need to talk to Maya about what Turner syndrome is.
Belinda: As I said, Turner syndrome is the presence of just one X chromosome instead of the standard two. It results in a female phenotype and it is predominantly a condition of infertility.
Belinda: Women with Turner syndrome usually have difficulties beginning puberty or going through puberty. They also tend to be quite short; they may be up to 20cm shorter than their expected height.
Belinda: There's a much higher risk of miscarriage with pregnancies carrying a baby with Turner syndrome.
Belinda: They may have heart defects and while their IQ is usually within the normal range, they may have some learning problems, usually specific to non-verbal and spatial learning, such as maths.
Belinda: Hormone treatments are available to help girls complete puberty and reach a maximum height, although it is unlikely to be within that sort of expected height.
Belinda: So, this is Hannah.
Belinda: Hannah was a 46-year-old female in her fifth pregnancy, but she has had four prior miscarriages.
Belinda: Her NIPT showed a high chance of Klinefelter syndrome.
Belinda: And, the positive predictive value was about 52%. By the time Hannah spoke to me, she was incredibly distressed and worked up, she had spent days on the Internet researching everything she could possibly find about Klinefelter syndrome and bizarrely autism.
Belinda: I find these sex chromosome abnormalities particularly difficult to counsel people on. Individuals often believe that because they are part of the NIPT panel of conditions that are screened.
Belinda: And because they are a chromosome abnormality, they must be considered of equal severity to Down syndrome, which is usually the only condition that they have heard of.
Belinda: In reality, people with Klinefelter syndrome, Turner syndrome, triple X syndrome are going about their everyday lives, often unaware of their diagnosis.
Belinda: Many individuals have very few complications other than potentially fertility issues. On the other hand, certainly some individuals do have problems and significant problems affecting their learning and health.
Belinda: Additionally, the literature is terrible in this area. The Internet is really cool when it comes to sex chromosomal abnormalities. Some websites are implying that Klinefelter syndrome results in homosexuality or aggressive violent behaviour even, both of which completely are untrue. Hannah came across literature or at least interpreted literature suggesting that all people with Klinefelter syndrome are autistic.
Belinda: Males with Klinefelter syndrome have two X and a Y instead of the standard single X and Y.
Belinda: Many appear to have no or very few complications. They do tend to be quite tall.
Belinda: They can have small testicles, reduced body hair, gynecomastia, all which can be treated if required by either testosterone treatment or surgery.
Belinda: Men with Klinefelter syndrome tend to require testosterone surgery to complete puberty and they are usually infertile.
Belinda: Their IQ again is within that sort of normal range, but they can have some learning specific problems.
Belinda: And those problems are often associated with language development and reading.
Belinda: When I am giving a result, I always think it is advisable to have some written information about a particular condition in question. I think reliable references are really important as well.
Belinda: And support groups can be really helpful. Keeping in mind that, by providing patients with information they are less likely to start googling things and particularly, the sex chromosome aneuploidies, I have got to say the Internet information out there can be really terrible.
Belinda: It is also quite biased we don't usually go around testing well-healthy individuals.
Belinda: So those individuals that are incorporated in studies and have been tested may have some underlying reason for being tested, so we might be seeing one end of the spectrum or a more biased population.
Belinda: In the same way, support groups are a little biased as well, because the individuals that either don't know they have condition or are getting along with their lives without too many complications tend to have less time to involve themselves in support groups.
Belinda: They certainly have their place, but I always let people know that they may potentially be looking at a bias group of individuals.
Belinda: So, Hannah's result came back after her CVS. I think the past FISH. FISH stands for fluorescent in situ hybridization. It is where you're attaching a little fluorescent probe to the chromosomes that you're interested in.
Belinda: Came back showing standard male chromosome pattern. FISH result usually comes back within about two to three working days.
Belinda: Your final chromosome analysis, whether it be a karyotype or a chromosomal microarray will come back in about 10 working days to two weeks. It too showed a standard male chromosome pattern.
Belinda: This is really great news for her, but I think sometimes it is difficult to undo that worry that they had begun with and so, it is really hard sometimes for patients who have had a false positive result to stop wondering was it something about this pregnancy that put them in an increased risk? Could there be something else that we haven't detected? Which result should they believe? So, talking to her about the fact that the analysis was actually performed on cells that represent the baby makes it a little bit more likely. Now, we may not get to the bottom of what was going on here, it could be a case of the mosaicism that we haven't detected. We may not ever be able to get back to the bottom of this, but the reason she had that diagnostic testing was to get the most accurate result that we could we give them.
Belinda: Now, I know we're running a bit late of time, but I did want to include 22q11.2 microdeletion syndrome because this is commonly included in a lot of NIPT panels.
Belinda: It is also known as DiGeorge syndrome, Shprintzen syndrome and velocardiofacial syndrome. It is known by that many different names because we used to consider them different conditions and that's an example of how incredibly variable this condition can be. We had identified individuals and then, subsequently tested their parents to find that one of the parents may have had this condition as well and didn't realise.
Belinda: So, it can be quite mild to a very multisystem disorder, causing potentially cleft lip or palate, heart defects, poor immune system, developmental delay and learning problems and increased risk of ADHD and autism, behavioural and emotional issues, mental health issues, the most common being depression and anxiety, 25% of people with this condition will develop schizophrenia.
Belinda: Importantly, the positive predictive value is 10% to 20%, so a person coming back with a high-risk result for this condition will have somewhere between 10% to 20% chance of babies affected, so an 80% to 90% chance the baby isn't.
Belinda: Loaded words and the language we use, this is kind of a difficult area because there's no hard and fast rules, what is acceptable for one individual may not be for another.
Belinda: Language is fluid and constantly changing. Terms that originated with medicine can then be misused and eventually become offensive in time. The term mongolism had previously been used to describe Down syndrome, and downers and mongoloids is now considered incredibly offensive. We also like to think of the person as being an individual in their own right, so we're not talking about a Down syndrome baby. We are talking about a baby with Down syndrome, a person with a difference.
Belinda: We avoid using terms like suffers from or is afflicted with.
Belinda: Even, the term risk can have negative connotations compared to chance.
Belinda: I know it starts sounding very difficult, but the concept of shoot the messenger is real and people giving the information for the first time and the language that they use is sometimes very difficult to come back from.
Belinda: People interpret risk in very different ways. A person's concept of a 10% chance of the baby having a problem is very different from a 90% chance the baby doesn't have a problem.
Belinda: Presenting information in terms of percentages versus odds ratios versus decimals is also you know difficult. We have talked a lot about sensitivity, specificity, positive predictive value and the average individual doesn't have a good understanding of these statistical terms either.
Belinda: I think that it is really difficult to judge how people might respond. I have certainly come across individuals who don't feel they could tolerate any differences and maybe would consider stopping a pregnancy or a missing digit on a fetus as opposed to others that may say, you know, 22q11 microdeletion syndrome, that's nothing I had a brother or a relative that had something that they consider much worse.
Belinda: Even the lethal conditions like trisomy 18 and trisomy 13, I wouldn't necessarily assume, because a person had an IPT that they would want to stop a pregnancy, despite those conditions not being compatible with life.
Belinda: The other complicated term is genetic. Things that are genetic are not always inherited and, in fact, for almost all the conditions we've been talking about tonight this is a really common misunderstanding because most of these conditions will happen for the first time in that individual and may not be something that is inherited from other family members.
Belinda: So, I usually think that a good place to start is listening to the language that your patients are using because that often tells you what is acceptable to them, whether they're talking about a fetus or whether they're talking about a baby.
Belinda: They can usually give you a pretty good understanding of what information they're willing to accept.
Belinda: Now, I have just thrown together a few resources that you might find helpful.
Belinda: One of the first points of call, I think should probably be the laboratory that performed the test. They usually have a number of resources, post-test resources, as well as pre-test resources that can help you. They usually have a staff that are very friendly and willing and very happy to talk about their testing.
Belinda: The situations where things are a little bit different. Maybe the dates were a little bit wrong or maybe an ultrasound is showing something unexpected. They always welcome that additional information and I have always found them very helpful. Genetic counsellors are also your friends as well. There are genetic services located all over Australia and you can find them at this link.
Belinda: Genetic counsellors don't necessarily need to have a patient referred to them.
Belinda: You may just wish to give them a call and say "Look, I've just got this result. I wonder if, you know, I'm interpreting it right or is there anything that you'd recommend or what time frame does my patient have to make decisions in this area?" and they are usually very happy to take phone calls and talk to you about that.
Belinda: The Center for Genetics education make some great fact sheets about the different conditions that we've been discussing. They also have some nice just generalist fact sheets about what are genes and chromosomes, and I find them very good resources.
Belinda: This is the website for the positive predictive value calculator and that's just a look at what it might show.
Belinda: The genetics in pregnancy is a CPD certified course run through the University of Melbourne and it is specifically designed for health professionals involved in maternity and prenatal care.
Belinda: The American Congress of Obstetricians and Gynaecologists have a nice resource and again, they have fact sheets that you can print.
Belinda: There is also this really quite fabulous resource called NIPT Insights which is a mobile app and it provides an educational tool for patients about testing and screening for chromosome abnormalities.
Belinda: That picture is my phone, I just logged on, it is free and it takes you through as a patient the potential questions you might want to ask or consider. It has got a number of resources. It also has a resource where you can store the questions that you want to ask your doctor when you go in and see them, so it is a tool that facilitates decision making.
Belinda: Of course, I am a resource. You are welcome to contact me. I can be of help hopefully and I think that there's a podcast that we will put up at the end that I hadn't had a lot of experience with but sounds really interesting called One Screened Every Minute and they will tell you a bit more about that at the end, but for now, maybe we'll open it up to questions if anybody has any.
Nicole: Thanks so much Belinda. We've had a few questions come through. The first is from Megan who asks, is the term chromosomal abnormality normally used when talking with the general public? Because, I tend to say genetic problems, so I guess you mentioned this a little bit as some difficulties with language, but what's the correct terminology we should be using in general?
Belinda: Well, I think that it depends on what we are talking about. When we are talking about NIPT, we are talking about chromosome abnormalities or chromosome changes. Genetic problems opens up to a much wider field and these conditions aren't covered by NIPT and I think it could potentially be a little bit misleading going back to that very first vignette where we have the woman that wants the test for everything. This won't actually pick up individual gene conditions or gene faults. It is only going to look at chromosome differences.
Nicole: Okay. Megan just wanted to add to her question that she has a very low literacy population so what's a simple, this is a loaded question, but what's a basic way that we can sort of get the message about NIPT across to people that are from a low-literacy background?
Belinda: It is hard because when we're looking at framing literacy for the general population even, we should be looking at aiming it for maybe an 11 or 12-year-old understanding, I think that's a good way to think about it. I usually explain that chromosomes are the packages that contain our genetic information and if we have too much of it, it can cause a problem and too little can cause a problem. You need to have just the right amount. And any extra or missing chromosome material can cause problems and people have often heard of Down syndrome. They may not have heard about other chromosome abnormalities, but most people seem to be familiar with Down syndrome and that's a good place to start. Have you heard of Down syndrome? This is caused by having too much genetic material and this is this test that we can screen for.
Nicole: Thanks. Anonymous would like to know about patient handouts if for a high risk NIPT result. You gave us quite a few resources there, what would you say the best place for us to go to for a fact sheet on high-risk results would be?
Belinda: Well, look the laboratories performing the tests often make very good resources, so that is a good place to start. I didn't mention this in my talk and I really meant to, I'm a big believer in allowing patients to have their own reports. I think that an awful lot of effort goes into the language and the way in which reports are written and I think if they have the report in their own hands, and they can take that home, it makes it an awful lot easier for them explaining it to other people. They can read usually the statistics for those people that really want to get in there and know every last detail about the test, they can do that. So, I like the idea of giving them the actual report, the resources provided by the laboratory that did the test. The Centre for Genetics Education, that was one of the resources that I listed, has really good information sheets. They are probably the places I would start. I think that's the easiest place to find good quality information.
Nicole: Okay. Dorothy asks "I recently saw a lady with a 1:12 risk of trisomy 21 which I'm presuming was on a combined first trimester screen but, NIPT was low risk, so what would your advice be if they have a high risk nuchal translucency and a low-risk NIPT?
Belinda: I would tell her that you're looking at two different screening tests that are screening in different ways, and neither is diagnostic so the only way of getting to the bottom of what's going on is to perform a diagnostic test if this patient actually wants that information. You could repeat either of those screening tests, again and again. It won't matter what the result is. One of those screening tests would have highlighted a high risk at one time, and you can't take that away, unfortunately without doing a diagnostic test.
Nicole: Okay, anonymous has asked when would you do maternal serum screening before or instead of an NIPT.
Belinda: It is interesting, I think, NIPT is very patient driven these days, but it comes at a cost, so there is a population of individuals that maybe won't want to pay for NIPT. There's value in maternal serum screening outside of looking at chromosome aneuploidy as well. And same with doing the 12-week ultrasound, so I would certainly say that I would always do the 12-week ultrasound in association with any other screening product that you're using, whether it be maternal serum screening or NIPT. You could choose maternal serum screening and NIPT. There is a chance you'll end up with the scenario we just heard before where you have two screening tests that show two different results, but either way, the solution will be a diagnostic test and it will give you the most information. There's value in both tools and it depends on the patient that you're talking to, and I really think it is probably a patient decision. I think what we've learned from ______ is that we should be talking about these patients, and we should be talking about their choices.
Nicole: Thank you. Erin Darney has asked quite a specific question. I recently had a patient whose husband had a relative with CDG. I believe the testing for this is only available at Westmead, is there any other testing that can be done for diseases like oscillation.
Belinda: So anytime, we have a genetic condition in a family we like to have molecular confirmation of the person that has the condition. For everybody else, this is aside from NIPT. This is not something an NIPT would be detecting. This is just a question about other genetic testing, so the principles for any condition with genetic testing if you have a family member that's affected by a particular condition and a person wanting any testing and a pregnancy, you need a molecular result, you need to know the genetic location of that era in the infected person before you can offer testing in a pregnancy.
Belinda: Once that's been confirmed that you can offer, you actually can identify the genetic cause because somebody may have a diagnosis without necessarily having a genetic mutation identified, only then can you offer testing and you would usually make sure that you had given the laboratories prior notice because they would need to receive a sample if we're talking about in a pregnancy by CVS or amniocentesis. They would need a sample from the mother as well to exclude any maternal cell contamination and they would probably want to know the exact location of both parents' mutations or one parent mutation depending on the condition we're talking about, so this is something that can't easily be done without having a genetic workup beforehand, so in these situations, we try as genetic counsellors to see these people before they're pregnant and to have done all the workup beforehand and in the cases where we haven't been able to do that and they are pregnant, then we've got time constraints whether we can actually offer a test in a pregnancy or sometimes we just might not be able to pull all those resources.
Belinda: In terms of laboratories, I can't answer specific questions about laboratories at this time, but there are many, many tests that we send overseas and don't use the strain laboratories for. There are also specialities within Australian laboratories, so we might send a sample to Perth because they are the lab that specialise in that particular condition.
Nicole: Okay, thank you. That's all the questions we have. So, can we please put up the information about the podcast?
Nicole: In the meantime, thank you very much to our webinar partner, Alumina. Thank you to everybody for attending and Belinda, a very special thank you to you. That has been a very informative presentation.
Nicole: So, on your screen, you will now see some information about the podcast that was mentioned earlier, One Screened Every Minute. Now, this is a podcast basically featuring ordinary people who've had some chromosomal differences in their pregnancies and they're sharing their stories really just so that we can all learn more about the experiences of people that have had some chromosomal abnormalities come up.
Nicole: Thank you, everybody again for joining us. Please have a good evening and take care.